Abstract
Nanomaterial (NM) surface chemistry has an established and significant effect on interactions at the nano-bio interface, with important toxicological consequences for manufactured NMs, as well as potent effects on the pharmacokinetics and efficacy of nano-therapies. In this work, the effects of different surface modifications (PVP, Dispex AA4040, and Pluronic F127) on the uptake, cellular distribution, and degradation of titanium dioxide NMs (TiO2 NMs, ~10 nm core size) are assessed and correlated with the localization of fluorescently-labeled serum proteins forming their coronas. Imaging approaches with an increasing spatial resolution, including automated high throughput live cell imaging, correlative confocal fluorescence and reflectance microscopy, and dSTORM super-resolution microscopy, are used to explore the cellular fate of these NMs and their associated serum proteins. Uncoated TiO2 NMs demonstrate a rapid loss of corona proteins, while surface coating results in the retention of the corona signal after internalization for at least 24 h (varying with coating composition). Imaging with two-color super-resolution dSTORM revealed that the apparent TiO2 NM single agglomerates observed in diffraction-limited confocal microscopy are actually adjacent smaller agglomerates, and provides novel insights into the spatial arrangement of the initial and exchanged coronas adsorbed at the NM surfaces.
Highlights
With the ever increasing prevalence of manufactured nanomaterials (NMs) and nanomedicines comes a pressing need for a comprehensive understanding of their interactions and behaviors in biological milieu [1,2,3]
Initial experiments to test the labeling of fluorescein isothiocyanate (FITC) serum were performed using uncoated (TiO2-un) and Dispex-AA4040-coated (TiO2-AA4040) TiO2 NMs, as representatives of bare and surface-modified NMs, respectively
Measurements showed no significant changes in particle size over time in the serum-containing medium (Supplementary Figure S4), changes in the agglomerate size were observed in artificial lysosomal fluid (ALF), suggesting that the changes observed in the live cell imaging were likely the result of uptake and trafficking-related changes in agglomerate size, followed by changes arising in the lysosomes
Summary
With the ever increasing prevalence of manufactured nanomaterials (NMs) and nanomedicines comes a pressing need for a comprehensive understanding of their interactions and behaviors in biological milieu [1,2,3]. A recent publication using the same particles as used here has shown that there are significant quantitative differences in the levels of fibrinogens, immunoglobulins, and several glycoproteins in the corona acquired from plasma [19]. These differences could correlate with different interactions with cell surface receptors, which have been observed previously, for example, with polysorbate-functionalized NMs preferentially adsorbing apolipoproteins aiding their passage across the blood–brain barrier [12]. It is likely that differences in the corona as a result of different polymer coatings may present different forms of receptor-mediated endocytosis
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